Brain Structure
and Social Anxiety

ARE SOME JUST BORN TO BE SHY?

There's new evidence that some people are born with a propensity to be shy.

Carl E. Schwartz of Harvard Medical School and colleagues conducted brain scans on 22 adults as they looked at pictures of familiar and unfamiliar faces.

The 13 subjects who had been shy at age 2 had more activity in a part of the brain known as the amygdala when they looked at unfamiliar faces than the nine subjects who had been outgoing toddlers. The amygdala regulates emotions, including, most prominently, fear.

"These findings support the hypothesis that ... some brain properties relating to temperament are preserved from infancy into early adulthood." the researchers wrote in reporting thir findings in the June 20 issue of the journal Science.

The researchers noted that many of the subjects who appeared to have been born shy were able to overcome that part of their temperaments as adults, even though their brains retained the tendency to react negatively to new faces.

"These findings may reflect a difference in vulnerability that can be compensated for or exacerbated by environment and experience." said Scott Rauch, who helped conduct the study.

Extreme shyness can lead to serious psychiatric disorders, such as social phobias or depression, the researchers said. Identifying the biological basis for shyness could lead to new and better treatments.

"It's only by understanding these developmental risk factors that one can really intervene in the lives of children early, to prevent suffering later in life," Schwartz said.

Infants with an inhibited temperament tend to develop into children who avoid people, objects, and situations that are novel or unfamiliar, whereas uninhibited children spontaneously approach novel persons, objects, and situations. Behavioral and physiological features of these two temperamental categories are moderately stable from infancy into early adolescence and have been hypothesized to be due, in part, to variation in amygdalar responses to novelty. We found that adults who had been categorized in the second year of life as inhibited, compared with those previously categorized as uninhibited, showed greater functional MRI signal response within the amygdala to novel versus familiar faces.

The term temperament refers to the stable moods and behavior profiles observed in infancy and early childhood. Although the notion of temperament is at least 2000 years old, dating back to the Greeks (1), the empirical studies of Chess and Thomas (2) sparked a renaissance of interest in infant temperaments. Two of the most extensively studied
temperamental constructs are related to the behavioral dimension of approach and withdrawal (2), which refers to the child's typical response to unfamiliar people, objects, and situations. The extremes of this dimension define two categories of children called behaviorally inhibited and uninhibited (1, 3, 4). Children with an inhibited temperament tend to be timid with people, objects, and situations that are novel or unfamiliar, whereas uninhibited children spontaneously approach novel persons, objects, and situations. These behavioral differences in young children
were accompanied by distinctive physiological differences, including differences in heart rate and heart rate variability, pupillary dilation during cognitive tasks, vocal cord tension when speaking under moderate stress,
and salivary cortisol levels (5, 6).

The footprint of these early individual temperamental differences is discernible in later childhood (7-11) and early adolescence (12-14). Furthermore, the two temperamental types are at risk for developing different symptom profiles. An uninhibited temperament in early childhood is associated, given particular rearing environments, with externalizing
behavior at adolescence (13), which ranges from display of a hot temper and stubbornness, to impulsive, aggressive, and antisocial behavior. In contrast, an inhibited temperament in early childhood is a risk factor for the development of one of the anxiety disorders in both children (15, 16) and adolescents (14), especially generalized social phobia alternatively termed social anxiety disorder) (14, 17).

The demonstration that these temperamental categories were heritable fueled interest in the basic brain properties that might mediate the temperamental biases observed in infancy (18, 19). It has been suggested that the complex behavioral and physiological profiles of these two temperamental categories might be the result of differing responses
to novelty in the amygdala (5, 6).

We tested this hypothesis with functional magnetic resonance imaging (fMRI) by measuring the response of the amygdala to novel versus familiar faces in 22 adults (mean age 21.8 years) who had been categorized in the
second year of life as inhibited (n = 13) or uninhibited (n = 9) (20).

The protocol (20) was divided into two portions: a familiarization phase and a test phase consisting of alternating blocks of either novel (N) or familiar (F) faces (Fig. 1A). The 96-s familiarization phase consisted of
16 presentations of six faces in pseudorandom order (balanced for gender and age). Each subject viewed four novel blocks; each block consisted of 24 different identities completely unique to that block, shown once, and never repeated, and four familiar blocks consisting of repeated presentation of the same six identities that had been presented repeatedly during the familiarization phase.

A repeated-measures analysis of variance (ANOVA) was performed (20) on the functional imaging data from a six-voxel region in the right amygdala and a three-voxel region in the left amygdala (Fig. 1B), and yielded a significant temperament X face-type interaction [F(1,20) = 4.21, P = 0.05]. The adult subjects categorized as inhibited in the second year of life showed a significantly greater response in both the right and left amygdalae to novel faces (versus fixation), compared with those subjects who had been categorized as uninhibited [Fig. 1C; t(20) = 2.40, P =
0.01]. By contrast, there was no difference between the two temperamental types in the amygdala signal when they viewed familiar faces (versus fixation). Furthermore, inhibited subjects showed significant signal increases in both the right and left amygdalae to novel versus familiar faces [Fig. 1C; t(12) = 3.13, P = 0.004], whereas adult subjects
categorized as uninhibited in the second year of life did not show a significant change in BOLD signal to novel versus familiar faces. The repeated-measures ANOVA affirmed that the responses in the right and left amygdalae were similar (21-23).

These findings support the hypothesis (5,6) that inhibited and uninhibited infants are characterized by different amygdalar responses to novelty and suggest that some brain properties relating to temperament are preserved from infancy into early adulthood. Only longitudinal studies can demonstrate developmental continuities from early childhood to adulthood and can affirm the persistent impact of a temperamental profile in adults. New developments in brain imaging technology will be required to probe directly for temperamental differences in amygdalar responses in infants.

An inhibited temperament is a risk factor for the development of generalized social phobia (14, 17), a psychiatric disorder characterized by persistent and pervasive fear of interaction with unfamiliar people and avoidance of situations where such interactions are anticipated. Two subjects in the present study, both categorized as inhibited in the second year of life, were diagnosed with generalized social phobia and showed signal changes comparable to the other inhibited subjects. We eliminated the possibility that the present results might be due to these two subjects by repeating the analyses without them. This analysis did not change the findings. These results imply that discovery of a difference in brain activity between subjects with a psychiatric diagnosis and a control group should not always be regarded as a specific marker of the disorder. The difference may reflect instead a temperamental risk factor, or diathesis, for the diagnostic category under study. Thus, the findings from crosssectional neuroimaging studies that describe differential amygdalar responses in subjects with social phobia (24-28) may be influenced by, or even due to, temperamental factors persisting from early in childhood. This fact suggests the need to study further the influence
of temperamental biases persisting from childhood on adult neuroimaging data.

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